Asymmetric C—H Functionalization of Indoles via Enantioselective Protonation

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Asymmetric C-H functionalization of indoles from Rh 2 (OAc) 4 and chiral phosphoric acid co-catalyzed reactions of aryl diazoacetates with indoles has been investigated.Through mechanistic study regarding to the proton transfer pathway of the C-H functionalization of indoles, a new strategy to achieve the asymmetric C-H functionalization of indoles from metal carbenoids via enantioselective protonation has been proposed.We initially carried out a deuterium isotope experiments in order to obtain more insight into the proton transfer process of the C-H functionalization of indoles, and the experiments indicated an "indirect proton transfer" in the reaction.A proton-transfer shuttle such as H 2 O was needed to complete the reaction.The observation provides us an opportunity to design a chiral proton-transfer shuttle to achieve the asymmetric C-H functionalization.In this paper, Rh 2 (OAc) 4 catalyzed diazo decomposition of a aryl diazoacetate generates a metal carbenoid.Reaction of the metal carbenoid with an indole at C-3 position generates a zwitterionic intermediate.A bifunctional chiral phosphoric acid serves as a chiral proton shuttle and helps the proton transfer process via an enantioselective protonation to finish the reaction in high yield and enantioselectivity.A number of indoles including N-alkyl, aryl , silyl and a number of α-aryl-α-diazoesters are well tolerated under the established catalytic conditions, providing good to high enantioselectivity (up to 94% ee) in excellent yield (up to 99% yield).A representative procedure for the enantioselective C-H functionalization of indoles is as following: A mixture of 6-chloro-N-methyl indole (1e) (41 mg, 0.25 mmol), transition metal catalyst Rh 2 (OAc) 4 (1 mg, 0.0025 mmol, 1 mol%), chiral phosphoric acid co-catalyst (R)-4j (3.8 mg, 0.005 mmol, 2 mol%) and 4Å MS (100 mg) in 1 mL of toluene was stirred at the 0 ℃.Methyl phenyldiazo acetate (2a) (53 mg, 0.3 mmol) in 1 mL of toluene was added over 1 h period of time via a syringe pump.After completion of the addition, the reaction was stirred for additional 5 min at the same temperature.Solvent was evaporated under reduced pressure to give corresponding crude product.The crude product was purified by flask chromatography on silica gel (eluent: EtOAc/light petroleum ether, V∶V＝1∶ 40～1∶10) to give the pure product 3q in 92% yield with 94% ee.